This invention relates to silicone rubber drug excipients having a regular, uniform and prolonged drug dispensation rate and medicines prepared with such excipients.
Organopolysiloxane elastomers are known to be suitable vehicles for depot drug preparations for long-term treatment in a living organism, since they are neither decomposed nor resorbed by the organism and exhibit good tissue compatibility in comparison with other synthetic polymers.
Nonionic, lipid-soluble drugs occluded in organopolysiloxane elastomers are delay released from the vehicle are described in Kincl et al., Steroids 11 (5) :675-680 (1968); Dzuik and Cook, Endocrinology 78: 208-211 (1966); Garrett and Chemburkar, J. Pharm. Sci. 57: 1401-1409 (1968).
Nonionic, lipophilic active drug agents are soluble in organopolysiloxane elastomers, the degree of solubility depending on the type of silicone elastomer. Consequently, the rate at which the drug is released from the silicone rubber vehicle depends substantially on the composition of this vehicle. The organic substituents in the polysiloxane employed must be selected so that no undesired side effects occur due to the presence of the polymer in the organism.
The use of solid organopolysiloxane elastomers as drug excipients for controllable release of effective agents is known and has been described, inter alia, in U.S. Pat. No. 3,279,996; British Pat. No. 998,794; and German Published Unexamined Application Nos. 1,912,343; 1,900,196; and 1,467,861.
The following organopolysiloxane elastomer raw materials are customary for the preparation of drug excipients:
Thermosetting organopolysiloxanes which are to be cured with peroxide catalysts, e.g., benzoyl peroxide or di-p-chlorobenzoyl peroxide, at temperatures of about 200.degree. C., and which require a heat aftertreatment; such organopolysiloxanes can be produced, for example, in accordance with U.S. Pat. Nos. 2,541,137; 2,890,188; 2,723,966; 2,863,846; and 3,002,951.
Furthermore, hydroxyl-terminated organopolysiloxanes of the room temperature vulcanizing (RTV) type have been employed which, after the addition of cross-linking agents in the presence of curing catalysts, harden at room temperature under atmospheric humidity into elastomers. Typical curing catalysts are metallic salts of a carboxylic acid, preferably tin salts, e.g., tin(II) octoate and tin(II)-2-ethylhexanoate.
One-component silicone rubber materials have also been used which set at room temperature under atmospheric humidity without any further additive. These one-component substances contain primarily organopolysiloxanes with two terminal-positioned acyloxy groups, e.g., acetoxy; the acyloxy groups are hydrolyzed under atmospheric humidity to form trifunctional siloxane units which cross-link the polymer into a cured elastomer. These organopolysiloxanes can be prepared, for example, according to U.S. Pat. Nos. 2,927,907 and 3,035,016, and British Pat. Nos. 798,669 and 804,199.
These latter polysiloxane elastomers are obtained by thermosetting linear organopolysiloxanes and are utilized only in the preformed vulcanized condition to prepare drug excipients. Vulcanization of organopolysiloxane containing the drug is impossible, since almost all useful drugs are unstable either at the required high vulcanizing temperature and/or in the presence of peroxide catalysts.
Capsule-shaped drug excipients of silicone rubber are known from the literature and have been described by Folkman and Long, JSR, VI (3): 139-142 (1966); Dzuik and Cook, Endocrinology 78: 208-211 (1966); Sundaram and Kincl, Steroids 12 (4): 517-524 (1968); Kratochvil et al., Steroids 15 (4): 505-513 (1970); and Croxatto et al., Amer. J. Obstet. Gyn. 105: 1135-1138 (1969).
These excipients are prepared by cementing the open ends of silicone rubber tubing into which the effective drug has been filled. A one-component silicone rubber material which sets at room temperature, e.g., RTV-silicone glue, is customarily employed for cementing purposes. Such capsule-like drug excipients cannot, however, be produced in satisfactory uniformity and numbers according to the process disclosed in the aforementioned German Published Unexamined Application No. 1,912,343. Furthermore, drug vehicles prepared from a silicone rubber tube by cementing with RTV-silicone glue have the disadvantage that the desirably high, prolonged regular release of effective agent from the carrier material cannot be attained. During the period of use, the packing density of the drug in the interior of the capsule is reduced, causing a marked reduction of the already relatively irregular release rate of effective agent. The irregular release rate of effective agent is compounded by the use of two differently structured types of silicone rubber as the vehicle for the effective drug agent. Customarily, the RTV-silicone adhesives utilized are cured at room temperature and under atmospheric humidity with acetic acid being split off, and the acetic acid vulcanization by-product can enter into undesired reactions with the drug. A further disadvantage of the above-described drug capsules is the poor mechanical properties of the slicone elastomer carrier material at the points of cementing.
The use of RTV-silicone rubber one-component materials alone is virtually impossible because they cannot be vulcanized in the layer thickness necessary for suitably strong excipients within a reasonable period of time and toxic by-products of the vulcanization process can adhere to the vulcanized product for an undesirably long period of time; the drugs are often unstable in the presence of these by-products.
By means of two-component RTV-type silicone rubber compositions which are cured to elastomers at room temperaure, drug excipients can be constructed according to the matrix principle in a technically simple manner. However, since the RTV-silicone rubber two-component compositions set to elastomers only in the presence of atmospheric humidity, these matrices cannot be produced in all desired shapes. Furthermore, many of the carboxylic acid metal salts customary as vulcanization accelerators are toxic to a living organism, as are the RTV-vulcanizates prepared therewith.
Silicone rubber vulcanizates can be produced in a hardness range of from 20 to 90 Shore A (DIN 53 505). As is known, vulcanizates of 45 to 70 Shore A exhibit the most favorable mechanical properties for use as a pharmaceutical excipient. However, the elastomers obtained from RTV-silicone rubber two-component mixtures exhibit only a hardness of 27-28 Shore A, and disintegrate into crumbs when subjected to only a slight to moderate mechanical stress. The loss of the original shape of the vehicle is then accompanied by an immediate and undesirable accelerated rate of drug release from the carrier material. Furthermore, large-volume drug excipients, e.g., larger than about a few millimeters in diameter, of an RTV type silicone rubber base have a strong tendency to depolymerize in the interior, resulting in reduced mechanical strength of the entire vehicle. In order to improve the mechanical properties it has been proposed to suspend fillers, e.g., highly dispersed silicon dioxide and the like, in the elastomer. However, the fillers often absorb the effective drug agent and thus impair the uniformity of drug release from the carrier material, and each drug-filler combination must be separately evaluated. The release of effective drugs from RTV-vulcanizates takes place in many cases at such high rates, as compared to the rates of release from heat-cured silicone rubber vulcanizates, that the formulation of excipients for the uniform release rate of the effective drug over a long term is impossible.